PEP-CMV + Nivolumab for Brain Cancer

(PRiME II Trial)

Recruiting at 2 trial locations

Overseen By Eric M Thompson, M.D.

Age: < 65

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Washington University School of Medicine

Must not be taking: Immunosuppressants, Tumor-directed therapy

Disqualifiers: Pregnancy, Active infection, HIV, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

68 Participants Needed

Trial Summary

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, it mentions that patients should not be on certain immunosuppressive agents or tumor-directed therapies. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the PEP-CMV + Nivolumab treatment for brain cancer?

Research suggests that targeting cytomegalovirus (CMV) antigens, which are present in glioblastoma (a type of brain cancer), can help the immune system recognize and kill cancer cells. This approach has shown promise in using the body's immune response to fight glioblastoma, indicating potential effectiveness for treatments like PEP-CMV. ^{1 2 3 4 5}

Is the combination of PEP-CMV vaccine and Nivolumab safe for humans?

Nivolumab (also known as Opdivo) is generally considered safe, but it can cause immune-related side effects, such as colitis (inflammation of the colon), which may require treatment with steroids. The PEP-CMV vaccine is still being studied, and while it shows promise in boosting immune responses, its safety profile in humans is not fully established yet. ^{6 7 8 9 10}

What makes the PEP-CMV + Nivolumab treatment unique for brain cancer?

The PEP-CMV + Nivolumab treatment is unique because it targets cytomegalovirus (CMV) antigens, which are present in glioblastoma (a type of brain cancer) but not in normal brain tissue, allowing the immune system to specifically attack the cancer cells. This approach combines a vaccine targeting CMV with Nivolumab, an immune checkpoint inhibitor, to enhance the immune response against the tumor. ^{1 2 11 12 13}

What is the purpose of this trial?

This is a multisite, phase I/II clinical trial in children and young adults with newly-diagnosed high-grade glioma (HGG), diffuse midline glioma (DMG) and recurrent HGG/DMG, Medulloblastoma (MB), or ependymoma (EPN) to determine the safety, immunogenicity, and efficacy of a CMV-directed peptide vaccine plus checkpoint blockade.

Research Team

Eric M Thompson, M.D.

Principal Investigator

Washington University School of Medicine

Eligibility Criteria

This trial is for children and young adults with new or recurrent high-grade gliomas, diffuse midline gliomas, medulloblastoma, or ependymoma. Participants must meet specific health criteria to ensure safety during the trial.

Inclusion Criteria

My cancer has spread to other parts of my body.

My bone marrow is functioning well.

Patients must be able to understand and sign an IRB approved written informed consent document

Exclusion Criteria

Patients with active unrelated systemic illness

I am currently undergoing treatment specifically for my tumor.

Pregnant or breast-feeding women

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction Treatment

Participants receive temozolomide and PEP-CMV vaccine during the induction cycle

11 weeks

Multiple visits for drug administration and monitoring

Maintenance Treatment

Participants continue to receive PEP-CMV vaccine every 28 days until recurrence or progression

Until progression

Monthly visits for vaccine administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 years

Treatment Details

Interventions

• Nivolumab
• PEP-CMV vaccine

Trial Overview The study tests a CMV-directed peptide vaccine (PEP-CMV) combined with Nivolumab, an immune checkpoint inhibitor. It also includes Temozolomide chemotherapy and a Tetanus booster to enhance the immune response.

Participant Groups

Group I: Phase II: Temozolomide + Nivolumab + PEP-CMV vaccine + Td booster Experimental Treatment 4 Interventions

Cycle 1 (Induction cycle) is 77±2 days. Will receive 1 course of temozolomide 200 mg/m\^2/day x 5 days on Days 1-5 of cycle 1 \& receive PEP-CMV vaccine at dose level 1 (250 μg/m\^2) on Days 21, 35 ±2 days, and 49 ±2 days. After the induction cycle, each subsequent cycle is 28 days. Starting in cycle 2, PEP-CMV vaccine is administered every 28 days on day 1 of each course. Patient can continue to receive PEP-CMV every 28 days until recurrence/progression. Patients will receive a tetanus (Td) booster at the time of enrollment. Immunotherapy begins with a Td pre-conditioning vaccine delivered 6-24 hours prior to the first vaccine on day 21. Patients will also receive nivolumab 3 mg/kg IV on day 14±1 day then every 14 days ±2 days thereafter.

Group II: Phase I Stratum III: Temozolomide + Nivolumab + PEP-CMV vaccine + Td booster Experimental Treatment 4 Interventions

Patients with recurrent/progressive MB or EPN with measurable disease can be enrolled at any point following recurrence regardless of any prior therapy. Cycle 1 (Induction cycle) is 77±2 days. Will receive 1 course of temozolomide 200 mg/m\^2/day x 5 days on Days 1-5 of cycle 1 \& receive PEP-CMV vaccine at dose level 1 (250 μg/m\^2) on Days 21, 35 ±2 days, and 49 ±2 days. After the induction cycle, each subsequent cycle is 28 days. Starting in cycle 2, PEP-CMV vaccine is administered every 28 days on day 1 of each course. Patient can continue to receive PEP-CMV every 28 days until recurrence/progression. Patients will receive a tetanus (Td) booster at the time of enrollment. Immunotherapy begins with a Td pre-conditioning vaccine delivered 6-24 hours prior to the first vaccine on day 21. Patients will also receive nivolumab 3 mg/kg IV on day 14±1 day then every 14 days ±2 days thereafter.

Group III: Phase I Stratum II: Temozolomide + Nivolumab + PEP-CMV vaccine + Td booster Experimental Treatment 4 Interventions

Patients with recurrent/progressive HGG or DMG with measurable disease can be enrolled at any point following recurrence regardless of any prior therapy. Cycle 1 (Induction cycle) is 77±2 days. Will receive 1 course of temozolomide 200 mg/m\^2/day x 5 days on Days 1-5 of cycle 1 \& receive PEP-CMV vaccine at dose level 1 (250 μg/m\^2) on Days 21, 35 ±2 days, and 49 ±2 days. After the induction cycle, each subsequent cycle is 28 days. Starting in cycle 2, PEP-CMV vaccine is administered every 28 days on day 1 of each course. Patient can continue to receive PEP-CMV every 28 days until recurrence/progression. Patients will receive a tetanus (Td) booster at the time of enrollment. Immunotherapy begins with a Td pre-conditioning vaccine delivered 6-24 hours prior to the first vaccine on day 21. Patients will also receive nivolumab 3 mg/kg IV on day 14±1 day then every 14 days ±2 days thereafter.

Group IV: Phase I Stratum I: Temozolomide + Nivolumab + PEP-CMV vaccine + Td booster Experimental Treatment 4 Interventions

Patients with newly-diagnosed high-grade glioma or DMG may be enrolled any time within 42 days after completing radiation. Cycle 1 (Induction cycle) is 77±2 days. Will receive 1 course of temozolomide 200 mg/m\^2/day x 5 days on Days 1-5 of cycle 1 \& receive PEP-CMV vaccine at dose level 1 (250 μg/m\^2) on Days 21, 35 ±2 days, and 49 ±2 days. After the induction cycle, each subsequent cycle is 28 days. Starting in cycle 2, PEP-CMV vaccine is administered every 28 days on day 1 of each course. Patient can continue to receive PEP-CMV every 28 days until recurrence/progression. Patients will receive a tetanus (Td) booster at the time of enrollment. Immunotherapy begins with a Td pre-conditioning vaccine delivered 6-24 hours prior to the first vaccine on day 21. Patients will also receive nivolumab 3 mg/kg IV on day 14±1 day then every 14 days ±2 days thereafter.

Nivolumab is already approved in United States, European Union, Canada, Switzerland for the following indications:

Approved in United States as Opdivo for:

• Advanced or metastatic gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma
• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Hepatocellular carcinoma
• Esophageal squamous cell carcinoma

Approved in European Union as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma

Approved in Canada as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma

Approved in Switzerland as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma

Who Is Running the Clinical Trial?

Washington University School of Medicine

Lead Sponsor

Trials

2,027

Recruited

2,353,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

Human cytomegalovirus (CMV) is found in glioblastoma (GBM) tumors but not in normal brain tissue, suggesting that CMV antigens could be effective targets for immunotherapy.

Research shows that T cells specific to the CMV pp65 antigen can recognize and kill GBM tumor cells derived from patients, supporting the potential for CMV-targeted immunotherapies in treating GBM.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunological targeting of cytomegalovirus for glioblastoma therapy. Nair, SK., Sampson, JH., Mitchell, DA.[2021]

DCVax-Brain, a personalized treatment using dendritic cells to target brain tumors, shows promise in inducing antitumor immunity with low toxicity in patients with glioblastoma multiforme (GBM).

Recent trials indicate that DC vaccine therapy correlates with clinical improvements in GBM patients, although some reports suggest possible selection bias in the findings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

DCVax-Brain and DC vaccines in the treatment of GBM. Wheeler, CJ., Black, KL.[2019]

Certain high-risk groups, such as HIV-infected individuals, transplant patients, and newborns, are particularly vulnerable to diseases caused by human cytomegalovirus (CMV), highlighting the need for effective vaccination strategies.

While there are currently no licensed CMV vaccines for humans, various vaccine approaches, including protein subunit, DNA, and live attenuated vaccines, are being tested in clinical trials, showing promise in inducing protective immune responses against CMV.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Progress toward an elusive goal: current status of cytomegalovirus vaccines. Schleiss, MR., Heineman, TC.[2007]

The novel PeptiENV cancer vaccine, which incorporates the MMR vaccine, significantly enhances both local and systemic immune responses against tumors when administered directly into the tumor.

Combining PeptiENV therapy with immune checkpoint inhibitors not only improves tumor control and survival rates in mice but also increases the effectiveness of the checkpoint inhibitors, showing that prior immunity to the MMR vaccine does not hinder the cancer treatment's efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A novel cancer vaccine for melanoma based on an approved vaccine against measles, mumps, and rubella. Fusciello, M., Ylösmäki, E., Feola, S., et al.[2022]

In a study of 119 patients with melanoma brain metastases, those who were asymptomatic showed a significant clinical benefit from the combination of nivolumab and ipilimumab, with a 36-month overall survival rate of 71.9%.

Symptomatic patients had much lower efficacy, with only 36.6% overall survival at 36 months, highlighting the challenges in treating symptomatic melanoma brain metastases with this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term outcomes of patients with active melanoma brain metastases treated with combination nivolumab plus ipilimumab (CheckMate 204): final results of an open-label, multicentre, phase 2 study. Tawbi, HA., Forsyth, PA., Hodi, FS., et al.[2022]

In a Phase II study involving 18 patients with leptomeningeal disease, the combination of ipilimumab and nivolumab showed promising efficacy, with 44% of patients alive at three months, surpassing the expected 18%.

The treatment had an acceptable safety profile, although one-third of patients experienced significant adverse events, including two cases leading to treatment discontinuation due to hepatitis and colitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of ipilimumab and nivolumab in leptomeningeal carcinomatosis. Brastianos, PK., Strickland, MR., Lee, EQ., et al.[2021]

References

1. United States pubmed.ncbi.nlm.nih.gov

Immunological targeting of cytomegalovirus for glioblastoma therapy. [2021]

2. United States pubmed.ncbi.nlm.nih.gov

Recognition and killing of autologous, primary glioblastoma tumor cells by human cytomegalovirus pp65-specific cytotoxic T cells. [2021]

3. United States pubmed.ncbi.nlm.nih.gov

Human cytomegalovirus-based immunotherapy to treat glioblastoma: Into the future. [2021]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Cytomegalovirus as a novel target for immunotherapy of glioblastoma multiforme. [2022]

5. England pubmed.ncbi.nlm.nih.gov

DCVax-Brain and DC vaccines in the treatment of GBM. [2019]

6. England pubmed.ncbi.nlm.nih.gov

Progress toward an elusive goal: current status of cytomegalovirus vaccines. [2007]

7. United States pubmed.ncbi.nlm.nih.gov

Intratumoral infection by CMV may change the tumor environment by directly interacting with tumor-associated macrophages to promote cancer immunity. [2018]

8. England pubmed.ncbi.nlm.nih.gov

Demarcated thresholds of tumor-specific CD8 T cells elicited by MCMV-based vaccine vectors provide robust correlates of protection. [2020]

9. Netherlands pubmed.ncbi.nlm.nih.gov

Desirability and feasibility of a vaccine against cytomegalovirus. [2022]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Cytomegalovirus Enterocolitis in a Patient with Refractory Immune-Related Colitis. [2020]

11. United States pubmed.ncbi.nlm.nih.gov

A novel cancer vaccine for melanoma based on an approved vaccine against measles, mumps, and rubella. [2022]

12. England pubmed.ncbi.nlm.nih.gov

Long-term outcomes of patients with active melanoma brain metastases treated with combination nivolumab plus ipilimumab (CheckMate 204): final results of an open-label, multicentre, phase 2 study. [2022]

13. England pubmed.ncbi.nlm.nih.gov

Phase II study of ipilimumab and nivolumab in leptomeningeal carcinomatosis. [2021]